1. Field of the Invention
This invention lies in the technology of synthetic processes for 4-sulfonamidophenyl hydrazines.
2. Description of the Prior Art
The compound 4-sulfonamidophenyl hydrazine and its various derivatives and analogs are useful for a variety of purposes. Some of these compounds are intermediates in the production of substituted phenyl pyrazolones, which serve a wide range of utilities extending from magenta color formers used in color photography to non-steroidal antiinflammatory drugs (NSAIDs) used for the inhibition of prostaglandins in the control of inflammation arising from arthritis and other physiological conditions. Disclosure of the use of 4-sulfonamidophenyl hydrazines in the synthesis of magenta color formers appears in U.S. Pat. No. 3,839,325 to Hoffstadt, Walter F. (GAF Corporation), issued Oct. 1, 1974, while disclosure of the use of these compounds in the synthesis of NSAIDs appears in U.S. Pat. No. 5,563,165 to Tally, John J., et al. (G. D. Searle & Co.), issued Oct. 8, 1996. The NSAIDs formed from 4-sulfonamidophenyl hydrazines are particularly useful for the selective inhibition of COX-2 relative to COX-1, both of which are cyclooxygenase enzymes that play key roles in the biosynthesis of prostaglandins.
The substituted phenyl pyrazolones that are used as COX-2 inhibitors and other therapeutic drugs often require administration in large doses over extended periods of time. It is therefore important that the drug and its intermediate be highly pure and capable of being synthesized free of impurities, in addition to being economical.
The most cost-effective synthesis of the 4-sulfonamidophenyl hydrazine intermediate is one in which the starting material is 4-chlorobenzenesulfonamide, since this material is both commercially available and readily prepared from the chlorosulfonation of chlorobenzene followed by reaction with ammonium hydroxide. A description of the conversion of 4-chlorobenzenesulfonamide (and its substituted analogs) to 4-sulfonamidophenyl hydrazine (and its substituted analogs) appears in the Hoffstadt patent cited above. The Hoffstadt process calls for the use of dimethyl sulfoxide (DMSO) as an aprotic dipolar solvent to enhance the nucleophilic character of the hydrazine. Unfortunately, the hydrazine, in addition to reacting with the 4-chlorobenzenesulfonamide, also reduced the DMSO to dimethyl sulfide and other by-products, resulting in a critically impure product.
A process that takes advantage of the low cost and availability of 4-chlorobenzenesulfonamide and yet produces a high product yield with little or no impurities is therefore needed.